The objective of the proposed research is to define those enzymes in lung (other than angiotensin coverting enzyme) which are responsible for the degradation of circulating vasoactive peptides. Bradykinin and angiotensin I are known to be metabolized by enzymes located on or near the plasma membrane of lung vascular endothethial cells. A considerable amount of evidence suggests that enzymes other than the well characterized angiotensin converting enzyme are significantly involved in this process. The principal Investigator has previously shown that a highly purified lung peptidase which appears to be localized on endothelial cell plasma membranes is capable of degrading both bradykinin and angiotensin I. The specific aims of the proposed research include further characterization of this peptidase as well as the identification and purification of additional membrane-bound peptidases which may be involved in the metabolism of vasoactive peptides. Cellular localization studies will be carried out to show which of these enzymes are localized near the site of peptide metabolism in vivo. The importance of the enzymes in the degradation of circulating peptides will be confirmed using perfused rat lung and intact animals by demonstrating that specific inhibitors of the purified peptidases are capable of inhibiting the pulmonary degradation of these peptides. Lung perfusion studies will also be used to determine if angiotension II can modify the levels of peptidase activity in the lung, thereby protecting itself from inactivation. Knowledge of the mechanism of vasoactive peptide metabolism in lung and characterization of the enzymes responsible may provide the rationale for therapeutic control of the levels and, hence, the physiological actions of vasoactive peptides.